Significance During coevolution with its host, human cytomegalovirus (HCMV) has invested a large part of its protein coding potential to ensure the dysregulation of the majority of cellular homeostatic circuits. Defining the role of these HCMV proteins is important to understand viral pathogenesis and to design new antiviral strategies able to exploit their functions. Here, we report on the functional characterization of the protein encoded by the US21 gene, the founding member of the HCMV US12 gene family. The pUS21 acts as a calcium-permeable multitransmembrane channel able to reduce the calcium content of intracellular stores; pUS21-mediated tampering with intracellular calcium homeostasis, in turn, decreases the cells’ susceptibility to apoptosis, thus contributing to the overall HCMV protein toolbox evolved to blunt apoptosis in infected cells.